Infection with Trypanosoma cruzi in women at reproductive age is associated with congenital transmission and adverse pregnancy outcome. The placenta is a key barrier to infection. We characterized gene expression profiles of term placental environment from T. cruzi seropositive (SP) and seronegative (SN) mothers performing RNA-seq. Nine pools of placental RNA paired samples were used: three from SN and six from SP tissues. Each pool consisted of female/male newborns and vaginal/caesarean deliveries binomials...

Choroid plexus tumors and ciliary body medulloepithelioma are predominantly pediatric neoplasms. Progress in understanding the pathogenesis of these tumors has been hindered by their rarity and lack of models that faithfully recapitulate the disease. Here, we find that endogenous c-Myc is down-regulated in the forebrain neuroepithelium, whose neural plate border domains give rise to anterior choroid plexus and ciliary body. To uncover the consequences of persistent MYC (c-Myc) expression, c-Myc expression was forced in multipotent neural precursors (Nestin-Cre:MYC), which produced a fully penetrant model of choroid plexus carcinoma and ciliary body medulloepithelioma...

MUC2 mucin is a large glycoprotein produced by goblet cells that forms the protective mucus blanket overlying the intestinal epithelium as the first line of innate host defense. High MUC2 production in inflammatory bowel disease and infectious colitis depletes goblet cells and the mucus layer by an unknown mechanism. Here, we analyzed the effect of high MUC2 biosynthesis on endoplasmic reticulum (ER) stress and apoptosis in goblet cells using a high MUC2-producing human goblet cell line (HT29-H) and a HT29-H clone (HT29-L) silenced for MUC2 expression by lentivirus-mediated shRNA...

Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsies showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages...

FHL2 is a multifunctional adaptor protein with fine-tuning adjustment properties. It acts as a regulator of signaling cascades but also as a cofactor of transcription and controls several anti-inflammatory immune responses. Recently, we described FHL2 as a novel regulator of influenza A virus propagation. We have shown that in vitro FHL2 restricts viral replication by accelerating the IRF-3-dependent transcription of the Ifnb1 gene. In this work, we unraveled an ambiguous role of FHL2 during influenza A virus infection in vivo...

MicroRNAs (miRNAs) are small noncoding RNAs involved in the posttranscriptional regulation of gene expression. Deregulated miRNA levels have been linked to Burkitt lymphoma (BL) pathogenesis. To date, the number of known pathogenesis-related miRNA-target gene interactions is limited. Here, we determined for the first time the miRNA targetomes of primary BL tumors and normal B cells. AGO2-RNA immunoprecipitation (AGO2-RIP) of two frozen diagnostic BL tissue samples and three CD19+ B-cell samples isolated from routinely removed tonsils revealed distinct miRNA targetomes of BL and normal B cells...

Dystrophic skeletal muscle is characterized by fibrotic accumulation of extracellular matrix components that compromise muscle structure, function, and capacity for regeneration. Tissue fibrosis is often initiated and sustained through transforming growth factor β (TGFβ) signaling, and KLF10 is an immediate early gene that is transcriptionally activated in response to TGFβ signaling. It encodes a transcriptional regulator that mediates the effects of TGFβ signaling in a variety of cell types. This report presents results of investigation of the effects of loss of KLF10 gene expression in wild-type and dystrophic (mdx) skeletal muscle...

Tumor invasion is a critical first step in the organismic dissemination of cancer cells and the formation of metastasis in distant organs, the most important prognostic factor and the actual cause of death in most of the cancer patients. We report here that the cell surface protein podoplanin (PDPN), a potent inducer of cancer cell invasion, is conspicuously expressed by the invasive front of squamous cell carcinomas (SCC) of the cervix in patients and in the transgenic HPV/E2 mouse model of cervical cancer...

Impairment of the intestinal mucosal immunity significantly increases the risk of acute and chronic diseases. Immunoglobulin A (IgA) plays a major role in humoral mucosal immunity to provide protection against pathogens and toxins in the gut. Here, we investigated the role of endogenous galectin-9, a tandem repeat-type β-galactoside-binding protein, in intestinal mucosal immunity. By mucosal immunization of Lgals9-/- and littermate control mice, it was found that lack of galectin-9 impaired mucosal antigen-specific IgA response in the gut...

Trefoil factors are small secreted proteins that regulate tissue integrity and repair at mucosal surfaces, particularly in the gastrointestinal tract. However, their relative contribution(s) to controlling baseline lung function or the extent of infection-induced lung injury are unknown issues. Using irradiation bone marrow chimeras, we found that Trefoil factor 2 (TFF2) produced from both hematopoietic- and non-hematopoietic-derived cells is essential for host protection, proliferation of alveolar type 2 cells, and restoration of pulmonary gas exchange following infection with the hookworm parasite Nippostrongylus brasiliensis...

High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...

Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear...

The pathological feature of intraductal papillomas is defined as a papillary structure composed of a fibrovascular stromal core lined by luminal epithelial cells and myoepithelial cells. We used droplet digital PCR for the mutational analysis of AKT1 (E17K) and PIK3CA (H1047R, E542K, and E545K) in 60 papillomas. AKT1 and PIK3CA mutations were detected in 12 (20%) and 17 (28%) of the papillomas, respectively. In five tumors harboring mutations, mutational analysis of AKT1 or PIK3CA was performed separately using luminal epithelial cells and myoepithelial cells sorted using anti-CK19 antibody and anti-SMA antibody...

Limited efficacy of clinical interventions for peripheral arterial disease (PAD) necessitates a better understanding of the environmental and genetic determinants of tissue pathology. Existing research has largely ignored the early skeletal muscle injury response during hindlimb ischemia (HLI). We compared the hindlimb muscle response, following six hours of ischemia, in two mouse strains that differ dramatically in their post-ischemic extended recovery: C57BL/6J and BALB/cJ. Perfusion, measured by laser Doppler and normalized to the control limb, differed only slightly between strains following HLI (<12% across all measures)...

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors...